The molecular events regulating early myeloid differentiation and commitment from the pluripotential hematopoietic stem cell are incompletely understood. Accumulating evidence suggests retinoic acid (RA) signaling plays a critical role in myeloid differentiation, likely through the transcriptional regulation of retinoic acid target genes. In preliminary work, we have identified a gene encoding a B-box zinc finger protein that is expressed during RA and IL3 induced myeloid differentiation of the murine EML (erythroid, myeloid and lymphoid potential) cell line. Additionally, this gene displays a unique mode of RA induced transcriptional regulation wherein RA and IL3 signaling synergize to transactivate this gene. The research goals of this proposal are to establish the role of this gene in myelopoiesis, and to dissect the mechanisms underlying its synergistic regulation by RA and IL3. Specifically, we propose to characterize the temporal and cell/tissue- specific pattern of expression of the gene and its product(s) in the mouse and in murine derived hematopoietic cell lines, and examine the effect of overexpression of the gene product(s) on hematopoietic/myeloid progenitor cell growth and differentiation in vitro. Promoter/regulatory genomic sequence of this, gene will be characterized to dissect the mechanism of RA and IL3 induced synergistic transactivation. The laboratory research will be performed by the principle investigator, Dr. Noel Maun, in conjunction with an educational program under the guidance of a sponsor, Dr. Nancy Berliner, and an advisory committee. In addition to the scientific goals, a further objective of this proposal is that it serves as a vehicle for the development of the candidate into an independent and productive investigator in the area of molecular hematopoiesis.
